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Parathyroid Hormone-Related Protein Markedly Potentiates Depolarization-Induced Catecholamine Release in PC12 Cells via L-Type Voltage-Sensitive Ca²⁺ Channels¹

Section of Endocrinology (M.L.B., A.E.B.), Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520; and The Kenneth S. Warren Laboratories (M.L.B.), Tarrytown, New York 10591

Address all correspondence and requests for reprints to: Michael L. Brines, Ph.D., M.D., The Kenneth S. Warren Laboratories, 765 Old Saw Mill River Road, Tarrytown, New York 10591. E-mail: mbrines{at}kswl.org

PTH-related protein (PTHrP) is a normal product of many excitable cells of the nervous and endocrine systems. Functions of PTHrP in these tissues are, however, currently unknown. Prior study has suggested that a relationship exists between PTHrP and the L-type voltage-sensitive Ca²⁺ channel (L-VSCC). For example, in cerebellar granule neurons PTHrP gene transcription is regulated by Ca²⁺ influx specifically through this channel. Amino-terminal PTHrP products signal via the widely expressed PTH/PTHrP receptor, which is linked to both protein kinase A and C. These second messengers are known modulators of L-VSCC conductance. To determine whether PTHrP can modulate L-VSCC function, we studied catecholamine secretion in a PC12 clone expressing the PTH/PTHrP receptor but not PTHrP. We found that PTHrP_(1–36) (100 nM) to be an ineffective secretagogue for resting cells, but its presence markedly potentiates secretion to K⁺ depolarization. The PTHrP-augmented catecholamine secretion depends entirely upon L-VSCC Ca²⁺ influx and rapidly inactivates. Similar effects were produced by (Bu)₂cAMP but not by carbachol. These observations support the hypothesis that PTHrP can regulate L-VSCC conductance. In the normal adrenal medulla that expresses both PTHrP and its receptor, PTHrP may act in an autocrine/paracrine fashion to modify catecholamine secretion.

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